1. Field
Provided is a polypeptide which specifically binds to and inhibits VEGF-C (Vascular endothelial growth factor-C), and a uses thereof. In particular, provided are a polypeptide that binds to VEGF-C (e.g., a VEGF-C antagonist), an anti-VEGF-C antibody, a method of inhibiting angiogenesis and a method of preventing, treating, and/or diagnosing a disease associated with activation and/or overexpression of VEGF-C, using the peptide or antibody.
2. Description of the Related Art
Angiogenesis refers to a physiological process through which new blood vessels form from pre-existing vessels, and plays an important role in formation of organs, normal physiological growth, wound healing, and the like. In addition, abnormal angiogenesis is critically involved in a disease such as tumor growth, development, or metastasis, age-related macular degeneration, diabetic retinopathy, psoriasis, rheumatic arthritis, chronic inflammation, and the like.
In particular, angiogenesis plays an important role in tumor growth or metastasis. For these reasons, various in-depth studies on the biological mechanisms involved in angiogenesis have been conducted by many global pharmaceutical companies. Most of the studies are based on the concept that inhibition or limitation of blood supply to tumor cells may lead to decreasing oxygen and nutrient supply to the tumor cells, thereby inhibiting the growth and proliferation of the tumor cells. One of targets of the studies is vascular endothelial growth factor (VEGF) family of which VEGF-A, VEGF-B, VEGF-C, VEGF-D have been identified.
Tumor metastasis to local lymph node through lymphatic vessel is a general step in cancer progress. The metastasis is an important prognostic factor in various cancers, and provides a standard for surgical and radiation therapy of local lymph node. The tumor metastasis occurs via local infiltration and destruction of intercellular matrix, intravasation into blood vessel, transport through lymph or other channel, survival in circulating blood, extravasation from blood vessel at secondary region, and proliferation at new location, in order (see Idler, et al., Adv. Cancer Res. 28, 149-250 (1978), Liotta, et al., Cancer Treatment Res. 40, 223-238 (1988), Nicolson, Biochim. Biophy. Acta 948, 175-224 (1988) and Zetter, N. Eng. J. Med. 322, 605-612 (1990)).
Recently, it has been reported that lymphangiogenesis and formation of lymphatic vessel promote the lymph node metastasis, and thus, the inhibition of lymphangiogenesis can provide a new strategy for preventing the lymph node metastasis in cancer therapy (Stacker et al., Nature Med. 7(2), 186-191 (2001); Skobe et al., Nature Med. 7(2), 192-8 (2001); Makinen et al., Nature Med. 7(2), 199-205 (2001)).
According to recent studies, the binding of VEGF-C, which is a member of VEGF family, and its receptor, VEGFR2 or VEGFR3, promotes lymphangiogenesis, and growth and migration of lymphatic endothelial cells (see Karkkainen M J, et al., Semin Cell Dev Biol. 13:9-18 (2002)). In addition, VEGF-C promotes breast cancer metastasis, human melanoma metastasis, and lymphatic-mediated metastasis by inducing tumor-related lymphangiogenesis in various solid cancers such as a gastric cancer, human colorectal cancer, infiltrative cervical cancer, and the like. In addition, overexpression of VEGF-C in cancer cells increases the tumor-related lymphangiogenesis, thereby promoting the metastasis to local lymph nodes (see Stacker S A., et al., FASEB J 16:922-34 (2002)). Furthermore, inhibition of VEGF-C/D mediated signaling in mice leads to inhibition of lymphangiogenesis and metastasis to lymph nodes (see He Y., et al., J Natl Cancer Inst. 94:819-25 (2002)).
Although VEGF-C has recently emerged as an important target in developing anti-angiogenesis drugs, there remains a need to develop more effective and potent VEGF-C targeting drugs.